Patel C

References (7)

Title : Central cholinergic transmission affects the compulsive-like behavior of mice in marble-burying test - Patel_2023_Brain.Res_1825_148713
Author(s) : Patel C , Patel R , Maturkar V , Jain NS
Ref : Brain Research , 1825 :148713 , 2023
Abstract : The presence of the cholinergic system in the brain areas implicated in the precipitation of obsessive-compulsive behavior (OCB) has been reported but the exact role of the central cholinergic system therein is still unexplored. Therefore, the current study assessed the effect of cholinergic analogs on central administration on the marble-burying behavior (MBB) of mice, a behavior correlated with OCB. The result reveals that the enhancement of central cholinergic transmission in mice achieved by intracerebroventricular (i.c.v.) injection of acetylcholine (0.01 microg) (Subeffective: 0.1 and 0.5 microg), cholinesterase inhibitor, neostigmine (0.1, 0.3, 0.5 microg/mouse) and neuronal nicotinic acetylcholine receptor agonist, nicotine (0.1, 2 microg/mouse) significantly attenuated the number of marbles buried by mice in MBB test without affecting basal locomotor activity. Similarly, central injection of mAChR antagonist, atropine (0.1, 0.5, 5 microg/mouse), nAChR antagonist, mecamylamine (0.1, 0.5, 3 microg/mouse) per se also reduced the MBB in mice, indicative of anti-OCB like effect of all the tested cholinergic mAChR or nAChR agonist and antagonist. Surprisingly, i.c.v. injection of acetylcholine (0.01 microg), and neostigmine (0.1 microg) failed to elicit an anti-OCB-like effect in mice pre-treated (i.c.v.) with atropine (0.1 microg), or mecamylamine (0.1 microg). Thus, the findings of the present investigationdelineate the role of central cholinergic transmission in the compulsive-like behavior of mice probably via mAChR or nAChR stimulation.
ESTHER : Patel_2023_Brain.Res_1825_148713
PubMedSearch : Patel_2023_Brain.Res_1825_148713
PubMedID: 38097126

Title : Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity - Atkinson_2023_Eur.J.Med.Chem_251_115132
Author(s) : Atkinson BN , Willis NJ , Zhao Y , Patel C , Frew S , Costelloe K , Magno L , Svensson F , Jones EY , Fish PV
Ref : Eur Journal of Medicinal Chemistry , 251 :115132 , 2023
Abstract : N-Acyl indolines 4 are potent, non-covalent Notum inhibitors developed from a covalent virtual screening hit 2a. The lead compounds were simple to synthesise, achieved excellent potency in a biochemical Notum-OPTS assay and restored Wnt signalling in a cell-based TCF/LEF reporter assay. Multiple high resolution X-ray structures established a common binding mode of these inhibitors with the indoline bound centred in the palmiteolate pocket with key interactions being aromatic stacking and a water mediated hydrogen bond to the oxyanion hole. These N-acyl indolines 4 will be useful tools for use in vitro studies to investigate the role of Notum in disease models, especially when paired with a structurally related covalent inhibitor (e.g. 4w and 2a). Overall, this study highlights the designed switch from covalent to non-covalent Notum inhibitors and so illustrates a complementary approach for hit generation and target inhibition.
ESTHER : Atkinson_2023_Eur.J.Med.Chem_251_115132
PubMedSearch : Atkinson_2023_Eur.J.Med.Chem_251_115132
PubMedID: 36934521
Gene_locus related to this paper: human-NOTUM

Title : A Devastating Neurological Disorder: Anti-Dipeptidyl-Peptidase-Like Protein 6 (DPPX) Encephalitis Causing Rapidly Progressive Dementia - Esechie_2023_Cureus_15_e51123
Author(s) : Esechie A , Thottempudi N , Patel C , Shanina E , Li X
Ref : Cureus , 15 :e51123 , 2023
Abstract : Rapidly progressive dementia (RPD) is caused by a heterogeneous group of neurological disorders, and the prototype is Creutzfeldt-Jakob disease (CJD). However, treatable causes including autoimmune encephalitis are often underrecognized and undertreated. A 72-year-old female patient was admitted with a 10-month history of rapidly progressive cognitive decline, visual hallucinations, paranoid behavior, diarrhea, and an 18-kg unintentional weight loss. On the physical exam, she was only oriented to the person and demonstrated an exaggerated startle response with diffuse rigidity. The initial clinical suspicion included CJD versus autoimmune encephalitis. Comprehensive laboratory testing, thyroid peroxidase, thyroglobulin antibodies, and autoimmune encephalitis panel were negative. The EEG showed mild to moderate diffuse slowing without any epileptiform abnormalities. An MRI brain revealed mild hippocampal atrophy. CSF testing revealed mild lymphocytic pleocytosis; RT-QuIC analysis and 14-3-3 protein were negative. There was no clinical improvement after treatment with IV steroids and IVIG. Repeated autoimmune encephalitis panel testing performed on a research basis was positive for dipeptidyl-peptidase-like protein 6 (DPPX) antibodies in serum and CSF. Unfortunately, our patient passed away before additional treatment could be attempted. Anti-DPPX encephalitis is a rare autoimmune disorder and an unrecognized cause of RPD. Early diagnosis and rapid escalation of treatment are imperative to avoid devastating neurological consequences.
ESTHER : Esechie_2023_Cureus_15_e51123
PubMedSearch : Esechie_2023_Cureus_15_e51123
PubMedID: 38274926
Gene_locus related to this paper: human-DPP6

Title : Effect of Shorea robusta resin extract in 3-nitropropionic acid-induced Huntington's disease symptoms in Sprague-Dawley rats - Patel_2023_Res.Pharm.Sci_18_303
Author(s) : Patel C , Thakur K , Shagond L , Acharya S , Ranch K , Boddu SH
Ref : Res Pharm Sci , 18 :303 , 2023
Abstract : BACKGROUND AND PURPOSE: Huntington's disease (HD) is a neurodegenerative disease characterized by neuronal death in the striatum. Asiatic acid is an active component of Shorea robusta (Dipterocarpaceae) plants with neuroprotective activity and is considered an acceptable therapeutic candidate for different neurodegenerative diseases. In the present study, the beneficial pharmacological action of Shorea robusta resin extract (SRRE) was assessed in 3-nitropropionic acid (3-NP)-induced HD in rats. EXPERIMENTAL APPROACH: The neuroprotective effect of SRRE (285.7 and 666.7 mg/kg, p.o., 14 days) was studied in 3-NP (10 mg/kg)-induced rats by measuring body weight, behavioral parameters including neurological scoring, motor coordination, spatial memory, and depression-like behavior, neuro-biochemical parameters (gamma-aminobutyric acid and acetylcholinesterase), and oxidative stress parameter in the brain. Histopathology of the rat's brain was also studied. FINDINGS/RESULTS: SRRE treatment (285.7 mg/kg and 666.7 mg/kg) substantially restored body weight, motor coordination, and mitochondrial enzyme complex I function and improved memory impairment as compared to 3-NP-treated rats. Furthermore, SRRE treatment significantly restored the antioxidant enzyme activity in brain tissue and ameliorated the histopathological changes induced by 3-NP. CONCLUSION AND IMPLICATIONS: The neuroprotective effect of SRRE on 3-NP-induced HD in rats was mediated by a reduction in oxidative stress which may favor the usefulness of Shorea robusta in HD.
ESTHER : Patel_2023_Res.Pharm.Sci_18_303
PubMedSearch : Patel_2023_Res.Pharm.Sci_18_303
PubMedID: 37593162

Title : Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity - Steadman_2022_J.Med.Chem_65_562
Author(s) : Steadman D , Atkinson BN , Zhao Y , Willis NJ , Frew S , Monaghan A , Patel C , Armstrong E , Costelloe K , Magno L , Bictash M , Jones EY , Fish PV , Svensson F
Ref : Journal of Medicinal Chemistry , 65 :562 , 2022
Abstract : Notum is a negative regulator of Wnt signaling acting through the hydrolysis of a palmitoleoylate ester, which is required for Wnt activity. Inhibitors of Notum could be of use in diseases where dysfunctional Notum activity is an underlying cause. A docking-based virtual screen (VS) of a large commercial library was used to shortlist 952 compounds for experimental validation as inhibitors of Notum. The VS was successful with 31 compounds having an IC(50) < 500 nM. A critical selection process was then applied with two clusters and two singletons (1-4d) selected for hit validation. Optimization of 4d guided by structural biology identified potent inhibitors of Notum activity that restored Wnt/beta-catenin signaling in cell-based models. The [1,2,4]triazolo[4,3-b]pyradizin-3(2H)-one series 4 represent a new chemical class of Notum inhibitors and the first to be discovered by a VS campaign. These results demonstrate the value of VS with well-designed docking models based on X-ray structures.
ESTHER : Steadman_2022_J.Med.Chem_65_562
PubMedSearch : Steadman_2022_J.Med.Chem_65_562
PubMedID: 34939789
Gene_locus related to this paper: human-NOTUM

Title : Acetylcholinesterase inhibitors combined with memantine for moderate to severe Alzheimer's disease: a meta-analysis - Glinz_2019_Swiss.Med.Wkly_149_w20093
Author(s) : Glinz D , Gloy VL , Monsch AU , Kressig RW , Patel C , McCord KA , Ademi Z , Tomonaga Y , Schwenkglenks M , Bucher HC , Raatz H
Ref : Swiss Med Wkly , 149 :w20093 , 2019
Abstract : BACKGROUND: The clinical efficacy and safety of combination therapy with acetylcholinesterase inhibitor (AChEI) and memantine compared to AChEI or memantine alone in patients with Alzheimer’s disease is inconclusive. AIMS OF THE STUDY: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the clinical efficacy and safety of combination therapy of AChEI and memantine to monotherapy with either substance in patients with moderate to severe Alzheimer's disease (Mini-Mental State Examination score is <20). METHODS: We systematically searched EMBASE, Medline and CENTRAL until February 2018 for eligible RCTs. We pooled the outcome data using inverse variance weighting models assuming random effects, and assessed the quality of evidence (QoE) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We included nine RCTs (2604 patients). At short-term follow-up (closest to 6 months), combination therapy compared to AChEI monotherapy had a significantly greater effect on cognition than AChEI monotherapy (standardised mean difference [SMD] 0.20, 95% confidence interval [CI] 0.05 to 0.35, 7 RCTs, low QoE) and clinical global impression (SMD −0.15, 95% CI −0.28 to −0.01, 4 RCTs, moderate QoE), but not on activities of daily living (SMD 0.09, 95% CI −0.01 to 0.18, 5 RCTs, moderate QoE) or behavioural and psychological symptoms of dementia (mean difference −3.07, 95% CI −6.53 to 0.38, 6 RCT, low QoE). There was no significant difference in adverse events (relative risk ratio 1.05, 95% CI 0.98 to 1.12, 4 RCTs, low QoE). Evidence for long-term follow-up (≥ 9 months) or nursing home placement was sparse. Only two studies compared combination therapy with memantine monotherapy. CONCLUSIONS: Combination therapy had statistically significant effects on cognition and clinical global impression. The clinical relevance of these effects is uncertain. The overall QoE was very low. With the current evidence, it remains unclear whether combination therapy adds any benefit. Large pragmatic RCTs with long-term follow-up and focus on functional outcomes, delay in nursing home placement and adverse events are needed.  .
ESTHER : Glinz_2019_Swiss.Med.Wkly_149_w20093
PubMedSearch : Glinz_2019_Swiss.Med.Wkly_149_w20093
PubMedID: 31269225

Title : Upstream sequencing and functional characterization of the human cholinergic gene locus - Hahm_1997_J.Mol.Neurosci_9_223
Author(s) : Hahm SH , Chen L , Patel C , Erickson J , Bonner TI , Weihe E , Schafer MK , Eiden LE
Ref : Journal of Molecular Neuroscience , 9 :223 , 1997
Abstract : The 5' flanking region of the human VAChT gene was sequenced to approx 5350 bases upstream of the initiating methionine codon of the VAChT open reading frame (orf). The 5' flanks of the human and rat cholinergic gene loci were compared to identify regions of local sequence conservation, and therefore of potential regulatory importance. Several discrete domains of high homology, including a cluster of far-upstream cis-active consensus motifs, a neuronally restrictive silencer element consensus sequence, and additional conserved sequences within the putative nerve growth factor response domain of the locus, were identified. The probable start of transcription of the VAChT gene was deduced from mapping of sequences of rat and human VAChT cDNAs onto the 5' flanking regions of the human and rat cholinergic gene loci. The actual utilization of a putative 5' VAChT exon in rat central nervous system (CNS) tissue was assessed by in situ hybridization histochemistry. RNA transcripts containing both VAChT and ChAT protein-coding sequences were abundant in spinal cord motoneurons, sympathetic preganglionic cells, basal forebrain, striatum, and cranial motor nuclei. R-exon-containing transcripts could be detected only at low levels in these cell groups, implying that most transcription of VAChT proceeds from a promoter downstream of the R-exon. To assess the structural requirements for expression of the VAChT gene without bias regarding the actual start of transcription, a 5' fragment of the human gene corresponding to approximately 3 kb of sequence extending upstream from within the presumed 5' untranslated region of VAChT itself was fused to a luciferase-encoding reporter and transfected into VAChT-expressing and nonexpressing human and rat cell lines. This portion of the VAChT gene provided strong promoter expression in both cholinergic and noncholinergic cell lines. Deletion of the putative neuronally restrictive silencer element (NRSE) resulted in enhanced transcription in all cell lines. Lack of differential expression of VAChT transcription in VAChT-expressing vs non-VAChT-expressing cell lines suggested that additional enhancer elements controlling cell-specific expression of the VAChT gene exist further upstream in the cholinergic locus 5' flank. Conservation of potential cis-active elements within a 1.4 kb sequence immediately upstream of the NRSE in both rat and human cholinergic gene loci suggests that this domain is required for cholinergic-specific regulation of VAChT and ChAT gene transcription.
ESTHER : Hahm_1997_J.Mol.Neurosci_9_223
PubMedSearch : Hahm_1997_J.Mol.Neurosci_9_223
PubMedID: 9481623